Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal diseases, and in the progression of tumour growth in
cancer, but current diagnosis and treatment remain inadequate.
Peptides derived from the 212
amino acid precursor
preproendothelin-1 (ppET-1) may have utility as
biomarkers, or cause
biological effects that are unaffected by
endothelin receptor antagonists. Here, we used specific immunoassays and LC-MS/MS to identify NT-proET-1 (
ppET-1[18-50]),
Endothelin-Like Domain Peptide (ELDP,
ppET-1[93-166]) and
CT-proET-1 (
ppET-1[169-212]) in
conditioned media from cultured endothelial cells. Synthesis of these
peptides correlated with ET-1, and plasma ELDP and
CT-proET-1 were elevated in patients with chronic
heart failure. Clearance rates of NT-proET-1, ELDP and
CT-proET-1 were determined after i.v. injection in anaesthetised rats.
CT-proET-1 had the slowest systemic clearance, hence providing a
biological basis for it being a better
biomarker of ET-1 synthesis. ELDP contains the evolutionary conserved
endothelin-like domain sequence, which potentially confers
biological activity. On isolated arteries ELDP lacked direct
vasoconstrictor effects. However, it enhanced ET-1 vasoconstriction and prolonged the increase in blood pressure in anaesthetised rats. ELDP may therefore contribute to disease pathogenesis by augmenting ET-1 responses.